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Current Oncology (Toronto, Ont.) Feb 2023Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and... (Review)
Review
Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Quality of Life; Transplantation, Autologous; Neoplasm Recurrence, Local
PubMed: 36826140
DOI: 10.3390/curroncol30020179 -
Technology in Cancer Research &... 2022Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 35903924
DOI: 10.1177/15330338221106563 -
Theranostics 2021The advanced, metastatic differentiated thyroid cancers (DTCs) have a poor prognosis mainly owing to radioactive iodine (RAI) refractoriness caused by decreased... (Review)
Review
Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS.
The advanced, metastatic differentiated thyroid cancers (DTCs) have a poor prognosis mainly owing to radioactive iodine (RAI) refractoriness caused by decreased expression of sodium iodide symporter (NIS), diminished targeting of NIS to the cell membrane, or both, thereby decreasing the efficacy of RAI therapy. Genetic aberrations (such as , , and RET/PTC rearrangements) have been reported to be prominently responsible for the onset, progression, and dedifferentiation of DTCs, mainly through the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Eventually, these alterations result in a lack of NIS and disabling of RAI uptake, leading to the development of resistance to RAI therapy. Over the past decade, promising approaches with various targets have been reported to restore NIS expression and RAI uptake in preclinical studies. In this review, we summarized comprehensive molecular mechanisms underlying the dedifferentiation in RAI-refractory DTCs and reviews strategies for restoring RAI avidity by tackling the mechanisms.
Topics: Autophagy; Cell Differentiation; Cell Membrane; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Iodine Radioisotopes; MicroRNAs; Neoplasm Proteins; Protein Transport; Receptors, Cytoplasmic and Nuclear; Receptors, Thyrotropin; Recombinant Proteins; Salvage Therapy; Signal Transduction; Symporters; Thyroid Neoplasms; Thyrotropin
PubMed: 33995657
DOI: 10.7150/thno.57689 -
The Korean Journal of Gastroenterology... Aug 2018Ascites is the most common cause of decompensation in cirrhosis, and 5% to 10% of patients with compensated cirrhosis develop ascites each year. The main factor of... (Review)
Review
Ascites is the most common cause of decompensation in cirrhosis, and 5% to 10% of patients with compensated cirrhosis develop ascites each year. The main factor of ascites formation is renal sodium retention due to activation of the renin-angiotensin-aldosterone system and sympathetic nervous system by the reduced effective volume secondary to splanchnic arterial vasodilation. Diagnostic paracentesis is indicated in all patients with a new onset of grade 2 or 3 ascites and in those admitted to hospital for any complication of cirrhosis. A serum-ascites albumin gradient of ≥1.1 g/dL indicates portal hypertension with an accuracy of approximately 97%. Sodium restriction, diuretics, and large volume paracentesis are the mainstay of treatment in grade 1 to 3 ascites. The refractoriness of ascites is associated with a poor prognosis with a median survival of approximately six months. Repeated large volume paracentesis plus albumin is the first line treatment, and liver transplantation is recommended in patients with refractory ascites. A careful selection of patients is also important to obtain the beneficial effects of transjugular intrahepatic portosystemic shunts in refractory ascites. This review details the recent diagnosis and treatment of cirrhotic ascites.
Topics: Ascites; Diuretics; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Transplantation; Severity of Illness Index
PubMed: 30145856
DOI: 10.4166/kjg.2018.72.2.49 -
Life (Basel, Switzerland) Nov 2023This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors... (Review)
Review
This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors (PIs) improve clinical outcomes in patients with myeloma; however, refractoriness to lenalidomide, a category of IMiD, predicts poor outcomes. Next-generation IMiDs, such as pomalidomide, are effective even for lenalidomide-refractory myeloma. Therefore, an IMiD-sequencing strategy from lenalidomide to pomalidomide would be desirable. PIs are an antimyeloma therapeutic agent with another mode of action that might restore cereblon, a target of IMiDs; therefore, an IMiD-free interval via class switching from lenalidomide to PIs may be a promising alternative for lenalidomide-refractory myeloma. Additionally, the anti-CD38 monoclonal antibody is a key drug for salvage therapy in anti-CD38 monoclonal antibody-naïve patients. In clinical practice, safety profiles and social convenience can play important roles in the choice of combination therapy. In the future, the selection of optimal treatments should be based on the status of the immunological environment and genetic alterations. This review aims to discuss IMiDs sequencing and IMiD-free interval strategies for lenalidomide- refractory myeloma.
PubMed: 38004369
DOI: 10.3390/life13112229 -
Science Advances Jun 2022We combine novel laboratory experiments and exospheric modeling to reveal that "dynamic" Ly-α photolysis of Plutonian methane generates a photolytic refractory...
We combine novel laboratory experiments and exospheric modeling to reveal that "dynamic" Ly-α photolysis of Plutonian methane generates a photolytic refractory distribution on Charon that increases with latitude, consistent with poleward darkening observed in the New Horizons images. The flux ratio of the condensing methane to the interplanetary medium Ly-α photons, φ, controls the distribution and composition of Charon's photoproducts. Mid-latitude regions are likely to host complex refractories emerging from low-φ photolysis, while high-φ photolysis at the polar zones primarily generate ethane. However, ethane being colorless does not contribute to the reddish polar hue. Solar wind radiolysis of Ly-α-cooked polar frost past spring sunrise may synthesize increasingly complex, redder refractories responsible for the unique albedo on this enigmatic moon.
PubMed: 35714189
DOI: 10.1126/sciadv.abq5701 -
EBioMedicine Jan 2024Migraine is a leading cause of disability worldwide. A minority of individuals with migraine develop resistant or refractory conditions characterised by ≥ 8 monthly... (Review)
Review
Migraine is a leading cause of disability worldwide. A minority of individuals with migraine develop resistant or refractory conditions characterised by ≥ 8 monthly days of debilitating headaches and inadequate response, intolerance, or contraindication to ≥3 or all preventive drug classes, respectively. Resistant and refractory migraine are emerging clinical definitions stemming from better knowledge of the pathophysiology of migraine and from the advent of migraine-specific preventive treatments. Resistant migraine mostly results from drug failures, while refractory migraine has complex and still unknown mechanisms that impair the efficacy of preventive treatments. Individuals with resistant migraine can be treated with migraine-specific preventive drugs. The management of refractory migraine is challenging and often unsuccessful, being based on combinations of different drugs and non-pharmacological treatment. Future research should aim to identify individuals at risk of developing treatment failures, prevent the condition, investigate the mechanisms of refractoriness to treatments, and find effective treatment strategies.
Topics: Humans; Migraine Disorders; Headache; Treatment Outcome; Treatment Failure
PubMed: 38142636
DOI: 10.1016/j.ebiom.2023.104943 -
Cancers Dec 2022Although lenalidomide-based combinations, such as lenalidomide plus a proteasome inhibitor or an anti-CD38 monoclonal antibody, improve the overall response rate,... (Review)
Review
Although lenalidomide-based combinations, such as lenalidomide plus a proteasome inhibitor or an anti-CD38 monoclonal antibody, improve the overall response rate, progression-free survival, and overall survival of patients with relapsed/refractory multiple myeloma (RRMM), there is a tendency to use these regimens as a frontline treatment. This strategy has led to the development of refractoriness early in the disease course, usually after the patient's first treatment. Since lenalidomide-free regimens have so far shown limited efficacy in lenalidomide-refractory patients, there is an unmet need for other treatment options. In this review, we discuss the therapeutic options available to treat the general population of lenalidomide-refractory patients (mono, double and triple refractory) and the subpopulation of patients with other high-risk features such as renal failure, extramedullary disease, and high-risk cytogenetics. Moreover, new promising individual therapies and the possible impact of immunotherapy in RRMM patients are debated.
PubMed: 36612152
DOI: 10.3390/cancers15010155 -
World Journal of Gastrointestinal... May 2014Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current... (Review)
Review
Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current therapies may fail in a proportion of patients. These patients deserve better evaluation and thorough investigations before their labeling as refractory to treatment. Indeed, several cases of apparent refractoriness are actually due to misconceptions about constipation, poor basal evaluation (inability to recognize secondary causes of constipation, use of constipating drugs) or inadequate therapeutic regimens. After a careful re-evaluation that takes into account the above factors, a certain percentage of patients can be defined as being actually resistant to first-line medical treatments. These subjects should firstly undergo specific diagnostic examination to ascertain the subtype of constipation. The subsequent therapeutic approach should be then tailored according to their underlying dysfunction. Slow transit patients could benefit from a more robust medical treatment, based on stimulant laxatives (or their combination with osmotic laxatives, particularly over the short-term), enterokinetics (such as prucalopride) or secretagogues (such as lubiprostone or linaclotide). Patients complaining of obstructed defecation are less likely to show a response to medical treatment and might benefit from biofeedback, when available. When all medical treatments prove to be unsatisfactory, other approaches may be attempted in selected patients (sacral neuromodulation, local injection of botulinum toxin, anterograde continence enemas), although with largely unpredictable outcomes. A further although irreversible step is surgery (subtotal colectomy with ileorectal anastomosis or stapled transanal rectal resection), which may confer some benefit to a few patients with refractoriness to medical treatments.
PubMed: 24868488
DOI: 10.4292/wjgpt.v5.i2.77